The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function*

Johnson, Heather; Swan, Suzanne K.; Heim‐Duthoy, Karen L.; Nicholls, Andrew; Tsina, Irene; Tarnowski, Thomas

doi:10.1016/s0009-9236(98)90102-3

Cited by 76 publications

(57 citation statements)

References 8 publications

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“…[30][31][32] We observed that there was a positive correlation between MPA and MPAG C 0 and serum creatinine concentration. C 0 of MPA and MPAG was influenced by renal function in CyA-treated recipients but not in those treated with TAC.…”

Section: Discussionmentioning

confidence: 60%

Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

Naito

Shinno

Maeda

et al. 2006

Biological & Pharmaceutical Bulletin

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Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) has been introduced into renal transplant immunosuppressant protocols in combination with calcineurin inhibitors (CNIs) and steroids. This study compared the pharmacokinetic profiles of MPA and its major metabolite MPA glucuronide (MPAG) in combination with tacrolimus (TAC) or cyclosporine (CyA) during the maintenance period (Ͼ6 months) following renal transplantation. There was no difference between TAC and CyA-treated groups in MPA plasma concentration before drug administration (C 0 ). MPA C 0 in TAC and CyA-treated patients did not differ from that in patients who were not treated with a CNI. In patients treated with a CNI, MPAG C 0 was significantly greater in those treated with CyA compared with TAC. The MPAG/MPA ratio in CyA-treated patients was significantly greater than that in the TAC-treated group. We observed that C 0 of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C 0 , MPAG C 0 and serum creatinine was stronger in patients treated with CyA compared with TAC. Our study suggests that CyA, but not TAC, inhibits enterohepatic circulation of MPAG as a secondary excretion pathway, and that renal function makes a major contribution to elimination of MPA and MPAG. We indicate that it may be necessary to estimate biliary excretion of MPAG to avoid the risk of intestinal injury in patients receiving combination therapy with TAC during the maintenance period.

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Section: Discussionmentioning

confidence: 60%

Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

Naito

Shinno

Maeda

et al. 2006

Biological & Pharmaceutical Bulletin

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“…Neither for RTX nor for AID a relationship between MMFdose per body weight and MPA-PK was found, suggesting that the initiation of MMF treatment in adults with a body weightadapted dosage is not of advantage compared with a fixed standardized dose. According to observations in transplant recipients (25), MPAG-AUC increased in both patient groups as renal function diminished. A higher glucuronidation of MPA has been described in male than in female RTX patients (30).…”

Section: Discussionmentioning

confidence: 89%

Pharmacokinetics of Mycophenolate Mofetil in Patients with Autoimmune Diseases Compared Renal Transplant Recipients

Neumann¹,

Haidinger²,

Jäger³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Mycophenolate mofetil (MMF), being effectively used as immunosuppressant in transplant medicine, has recently attracted interest as therapeutic agent for autoimmune diseases (AID). For these patients, no pharmacokinetic (PK) data are available. This study is an investigation of single-dose concentration-time profiles of 1 g off MMF in 16 patients with AID, including 10 patients with ANCA-associated vasculitis and 6 patients with systemic lupus erythematosus, and compares them with profiles of 16 renal transplant recipients (RTX). Mycophenolic acid (MPA) blood levels were measured by both HPLC and EMIT, and MPA-glucuronide was determined by HPLC. In AID, mean MPA concentrations at 12 h were significantly higher compared with RTX (4.1 Ϯ 3.27 versus 1.8 Ϯ 1.15 mg/L; P ϭ 0.018), whereas peak concentrations were lower (P ϭ 0.017). However, mean MPA-AUC at 12 h as well as at 24 h were comparable between both groups. In contrast to RTX, there was an association in AID between MPA trough levels at 12 h and at 24 h with AUC 0-12 (P Ͻ 0.05 and P Ͻ 0.01). MPA trough concentrations at 24 h provided an estimation of AUC 0-24 h in both patient groups (P Ͻ 0.001 and P Ͻ 0.01; AID and RTX, respectively). Compared with RTX, MPA-PK seems to be less affected in AID by renal function. Inter-individual variability of PK parameters was high in both groups. These data indicate that there are differences of MPA-PK between RTX and AID. The use of therapeutic drug monitoring in patients with AID appears to be clinically practicable and may be valuable to optimize individual immunosuppressive therapy.The positive experience with mycophenolate mofetil (MMF) in the field of solid organ transplantation made this drug attractive for the treatment of several autoimmune diseases (1-4). Promising data derived from pilot studies suggests a therapeutic potential of MMF in the treatment of ANCA-associated small vessel vasculitis (ASVV) and systemic lupus erythematosus (SLE) (5,6). In a randomized trial from Hong Kong comparing MMF with cyclophosphamide in patients with diffuse proliferative lupus nephritis, remission and relapse rate were comparable in both groups, whereas MMF was better tolerated (7). Nevertheless, for these patients neither recommendations for optimal dosage of MMF nor data concerning drug exposure of MMF are available.In kidney transplant recipients, several studies have shown a relationship between pharmacokinetic (PK) parameters with efficacy and toxicity. While patients with a low area under the concentration-time curve (AUC) of the active metabolite mycophenolic acid (MPA) appear to be at high risk for experiencing graft rejection (8), a relationship between MPA-PK and adverse effects has been found (9). Higher dosages like 3 g/d were associated with an increased occurrence of adverse effects; therefore, MMF is usually administered at a fixed daily dose of 2 g/d divided into two applications (10). However, the considerable individual variability and changes over time of PK parameters of MPA (10,11) as well as drug ...

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“…For example, some studies found that impaired renal function and low albumin levels result in high total MPA clearance and thus low total MPA exposure (5,9,11,13,14), although this could not be confirmed in all stud-ies (15)(16)(17)(18)(19)(20). Also with regard to the effect of the use of comedication (3,10,18,21,22), diabetes (23,24), body weight (11,13,17,20), age (5,11,18 -20), gender (11,20,23), and race (9,23,25), contrasting results have been obtained. Most of these studies were underpowered, based on MPA predose levels only, and some studies did not control adequately for confounding factors.…”

mentioning

confidence: 96%

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

Hest¹,

Mathôt²,

Pescovitz

et al. 2006

Journal of the American Society of Nephrology

177

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Large between-and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P < 0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

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The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function*

Cited by 76 publications

References 8 publications

Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

Pharmacokinetics of Mycophenolate Mofetil in Patients with Autoimmune Diseases Compared Renal Transplant Recipients

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

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